WO2018080214A1 - Formulation pour absorption percutanée pour le traitement de troubles du sommeil - Google Patents

Formulation pour absorption percutanée pour le traitement de troubles du sommeil Download PDF

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Publication number
WO2018080214A1
WO2018080214A1 PCT/KR2017/011961 KR2017011961W WO2018080214A1 WO 2018080214 A1 WO2018080214 A1 WO 2018080214A1 KR 2017011961 W KR2017011961 W KR 2017011961W WO 2018080214 A1 WO2018080214 A1 WO 2018080214A1
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WO
WIPO (PCT)
Prior art keywords
group
agent
weight
percutaneous absorption
film
Prior art date
Application number
PCT/KR2017/011961
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English (en)
Korean (ko)
Inventor
이정식
이순호
한문석
이우영
김상린
김한기
Original Assignee
신신제약 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020170138990A external-priority patent/KR102499141B1/ko
Application filed by 신신제약 주식회사 filed Critical 신신제약 주식회사
Priority to EP17864720.2A priority Critical patent/EP3533443B1/fr
Priority to CN201780067578.0A priority patent/CN110022864B/zh
Priority to US16/345,948 priority patent/US20210154153A1/en
Publication of WO2018080214A1 publication Critical patent/WO2018080214A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug

Definitions

  • the present invention contains melatonin as an active ingredient in order to increase the patient's compliance with medication, and even when the drug is contained in a high concentration in the adhesive matrix, the drug is stably maintained without generating crystals and the effective drug is introduced into the body through the skin. It relates to a melatonin transdermal absorption agent that can be delivered.
  • Melatonin is a hormone secreted from the pineal gland of mammals and has a photoperiodic characteristic in which secretion is regulated according to the circadian rhythm.
  • the concentration of melatonin in plasma begins to increase at around 9 pm and reaches its maximum between 2 and 4 am and returns to its original concentration between 7 and 9 am.
  • Melatonin has a sleep-inducing effect and is used to treat insomnia and sleep disorder patients. However, melatonin undergoes severe liver-first pass upon oral administration, and has a short half-life of about 1 hour, resulting in low bioavailability and large fluctuations in blood concentration. Therefore, the bioavailability is also reported to be only 20%.
  • Reservoir type transdermal absorption preparations consist of a drug-containing storage layer on a gel, a release control membrane that regulates the release of the drug, and an adhesive that adheres to the skin, which can damage the reservoir during storage or use, If the reservoir is broken, there is a problem that the drug may be absorbed beyond the reference value, which may cause a patient risk.
  • transdermal absorbents as described above, drug release control, high stability, easy storage and use, and easy development of melatonin transdermal absorbents.
  • the present invention is to provide a monolithic thin melatonin transdermal absorbent preparation having high safety, easy to store and use, by combining safety-proven raw materials.
  • the monolithic transdermal absorbent is capable of storing and stabilizing the drug in one adhesive layer, and controlling transdermal absorption.
  • the inventors of the present invention provide a monolithic thin film melatonin transdermal absorption agent in which the stability of the drug is improved by combining a suitable adhesive and a raw material without taking a reservoir type, and the drug is constantly delivered through the skin. Completed.
  • Melatonin transdermal absorption preparation according to the present invention is capable of controlling drug release, high stability, easy storage and use, and is easy to manufacture.
  • the percutaneous absorption preparation according to the present invention can significantly improve the compliance of the patient to the oral medication, while delivering the required amount of the drug to the patient can be useful in the treatment of insomnia and sleep disorders.
  • after removal, residuals in the skin can be minimized.
  • A is a support layer
  • B is a drug-containing adhesive layer
  • C is a release layer.
  • Example 2 is a graph showing cumulative transdermal absorption for Examples 18 to 23 and Comparative Example 3 of the present invention.
  • Figure 3 is a graph showing the cumulative transdermal absorption for Examples 24 to 29 of the present invention.
  • the present invention relates to a transdermal absorption preparation using melatonin as an active ingredient, and more particularly, to a melatonin transdermal absorption preparation in a monolithic form.
  • the transdermal absorption preparation of the present invention comprises: (a) a drug-containing adhesive layer containing melatonin or a pharmaceutically acceptable salt thereof, and a polymer adhesive agent as an active ingredient; (b) a support layer; And (c) a release layer, which may be used for the treatment of insomnia and sleep disorders.
  • the drug-containing adhesive layer in addition to melatonin or a pharmaceutically acceptable salt thereof, and a polymer adhesive base, may further include a dissolution aid, a crystal inhibitor, a transdermal absorption enhancer, and an antioxidant.
  • any pressure-sensitive adhesive may be used without limitation, it is preferable that an acrylic pressure-sensitive adhesive is used.
  • the acrylic pressure-sensitive adhesive which can be used in the present invention is an acrylic polymer adhesive agent comprising an acrylate or a copolymer of vinyl acetate and acrylate, and includes (i) no functional group, and (ii) a hydroxyl (-OH) group as the functional group.
  • One or two or more selected from the group consisting of (iii) having a carboxyl (-COOH) group as a functional group, and (iv) having both a hydroxyl group and a carboxyl group as a functional group can be used.
  • an acrylic pressure sensitive adhesive having a carboxyl group (-COOH) or simultaneously containing a carboxyl group and a hydroxyl group (-OH) may be used.
  • melatonin Since melatonin has a part having a non-covalent electron in its structure, a pressure sensitive adhesive having a hydroxyl group having a lot of electrons is advantageous for transdermal absorption, but may cause a problem that crystals are easily generated, and a non-functional acrylic pressure sensitive adhesive Due to the functional group of melatonin, the solubility of the pressure-sensitive adhesive itself is lowered, which may cause a problem that crystals are easily generated.
  • the pressure-sensitive adhesive having a carboxyl group it is possible to dissolve the drug by acting with the functional group of melatonin, and the use of some dissolution aids and crystal inhibitors can effectively suppress the crystal formation of the main component.
  • the polymer adhesive base used in the present invention may be a pressure-sensitive adhesive agent having a hydrophobic polymer as a periodic agent.
  • the hydrophobic polymer include polyisoprene, polyisobutylene, polybutadiene, polystyrene butadiene copolymer, polystyrene isoprene copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, butyl rubber, natural rubber, One or two or more kinds selected from the group consisting of ethylene vinyl acetate copolymers, polysiloxanes and methacrylic acid polymers can be used.
  • the polymer adhesive may further include a tackifying resin and a plasticizer, wherein the hydrophobic polymer may be 20 to 60% by weight, the tackifying resin is 20 to 50% by weight, and the plasticizer may be included as 2 to 30% by weight. .
  • Acrylic pressure-sensitive adhesives are preferred in view of solubility or adhesion of the drug.
  • a dissolution aid may be used for the stable dissolution of melatonin in the transdermal absorption preparation.
  • pyrrolidone derivatives, glycols, propylene carbonate, ethers, polyoxyethylene fatty acid esters can be used, and preferably N-methylpyrrolidone , Dipropylene glycol, Propylene glycol, Propylene carbonate, Ethoxydiglycol, Diethylene glycol monoethyl ether, Triacetin, Tri Triethyl citrate, trolamine, tromethamine, bis-Tris, aminomethyl propanediol, aminoethyl propanediol, polyoxyethylene Sorbitan monooleate, PEG-8 caprylic / capric glycerides 1 uses alone or in combination of two or more.
  • the dissolution aid of the present invention is used to 1 to 30% by weight based on the total weight of the drug-containing adhesive layer, preferably 1 to 15% by weight. If more than 30% by weight, there is a possibility of damaging the user's skin, may lower the physical strength of the transdermal absorbent.
  • the crystal inhibitor may be used to 0.05 to 5% by weight based on the total weight of the drug-containing adhesive layer, preferably 0.05 to 2.5% by weight. Since the crystal inhibitor is a polymer, it may cause problems such as acrylic adhesive and entanglement when used at 5% by weight or more, and may also decrease the adhesive strength.
  • the percutaneous absorption enhancer may further include a percutaneous absorption enhancer.
  • a percutaneous absorption enhancer fatty acid esters, nonionic surfactants, pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid ethers can be used, and fatty acid esters are preferably used.
  • Aliphatic derivatives of C 8-18 that can be used as transdermal absorption enhancers in the present invention include glycerol lauryl alcohol, oleyl alcohol, myristic acid and isopropyl myristate.
  • glycerol monooleate glycerol monolaurate, propylene glycol monolaurate, sorbitan monooleate, sorbitan monolaurate, corn oil PEG-8 ester and One or two or more kinds selected from the group consisting of corn oil PEG-6 ester can be used.
  • Transdermal absorption enhancer of the present invention may be used 1 to 30% by weight, preferably 1 to 15% by weight based on the total weight of the drug-containing adhesive layer. If the percutaneous absorption enhancer exceeds 30% by weight, the percutaneous absorption of the drug is no longer improved, which may lead to a decrease in the physical strength of the percutaneous absorption preparation, and in some cases may cause a user's skin trouble.
  • the present invention may further include an antioxidant to inhibit degradation and denaturation in the melatonin transdermal absorbent. Since melatonin also acts as a radical scavenger for oxygen radicals in the body, it may contain antioxidants or equivalent antioxidants to inhibit the reaction with oxygen.
  • Antioxidants include Butyl hydroxy toluene, Butyl hydroxy anisole, Propyl galate, Ascorbic acid, Tocopherol, Tocopherol acetate acetate) and ascorbyl palmitate, one or two or more selected from the group consisting of can be used, and preferably butylhydroxytoluene, tocopherol, tocopherol acetate, butylhydroxyanisole is used. .
  • Antioxidant may be used to 0.1 to 5% by weight relative to the total weight of the drug-containing adhesive layer, preferably may be used to 0.1 to 1% by weight. If more than 5% by weight of antioxidant is used, the antioxidant effect is no longer improved.
  • Melatonin or a pharmaceutically acceptable salt thereof in the drug-containing adhesive layer in the present invention may be included in 3 to 20% by weight relative to the total weight of the drug-containing adhesive layer.
  • the drug-containing adhesive layer may further include a dissolution aid, a crystal inhibitor, a percutaneous absorption enhancer, and an antioxidant in the weight ratio mentioned above, and may be further added (50 to 94.85% by weight). It may include a polymer adhesive of.
  • the support layer is used to prevent the loss of melatonin from the preparation during attachment or storage to the skin, to use a thin, flexible and does not cause an allergic reaction to the skin.
  • materials such as polyethylene terephthalate (PET), polyethylene (PE), polypropylene (PP), ethylene vinyl acetate copolymer (EVA), nylon (Nylon), etc. may be used.
  • Laminated films in which more than one film is combined can be used.
  • a film in which aluminum is deposited may be used to block light and moisture permeation.
  • a thin nonwoven fabric or cotton cloth, fabrics, etc. may be laminated on such a film, and the above-mentioned fabric may be used alone.
  • the release layer is not particularly limited as long as it protects the drug-containing product while the product is packaged or stored, and provides convenience so that it can be easily removed when using the product.
  • stacked with quality paper, glassine paper, and polyolefin can be used.
  • the release film is a surface of the adhesive layer coated with a silicone resin or a fluororesin, and it is preferable to use a polyethylene terephthalate film having excellent long-term stability of the drug.
  • the best percutaneous absorption was Duro-Tak TM 87-2516, but crystals precipitated.
  • Pressure-sensitive adhesive that is not precipitated crystals are Duro-Tak TM 87-2074, Duro-Tak 87-2852, and TM is a percutaneous absorption was Duro-Tak TM 87-2074 is higher than Duro-Tak TM 87-2852 comparative example rubber-based pressure-sensitive adhesive dermal Absorption was good but crystals precipitated.
  • N-methylpyrrolidone, Transcutol CG, and dipropylene glycol did not form crystals with the naked eye when observing the manufactured patches, but microscopic crystals were observed under the microscope and yellowing was observed in the prepared patches. Therefore, in order to effectively suppress the formation of crystals in the patch, additional researches on crystal inhibitors and antioxidant prescriptions to prevent yellowing were conducted.
  • the crystallization inhibitor was added to the 70mL vial to dissolve, and then dissolved in a dissolution aid, antioxidant, and melatonin, and then mixed with a roll mixer for 2 hours. After leaving for 30 minutes to remove the air bubbles, the polyethylene terephthalate release film treated with silicon on the coating machine and the blended pressure-sensitive adhesive was coated to 70 ⁇ m after drying. Thereafter, after drying for 3 minutes in an oven at 80 ° C., the support layer film was laminated and pressed using a compression roller, and then a patch having an area of 10 cm 2 was produced using a patch cutter.
  • Table 3 The compounding amount according to each example is shown in Table 3 below, and then the physical properties and crystal formation of the patch were observed. Observation and experimental results are also shown in Table 3 below.
  • the crystallization inhibitor was added to the 70mL vial to dissolve, and then dissolved in a dissolution aid, antioxidant, transdermal absorption enhancer, and melatonin, and then mixed in a roll mixer for 2 hours. After leaving for 30 minutes to remove the air bubbles, the polyethylene terephthalate release film treated with silicon on the coating machine and the blended pressure-sensitive adhesive was coated to 70 ⁇ m after drying. Thereafter, after drying for 3 minutes in an oven at 80 ° C., the support layer film was laminated and pressed using a compression roller, and then a patch having an area of 10 cm 2 was produced using a patch cutter.
  • Table 4 The compounding amount according to each example is shown in Table 4 below, after which the physical properties and crystal formation of the patch were observed, and transdermal absorption experiment was performed. Observation and experimental results are also shown in Table 4 and FIG. 2 below.
  • the prepared patch was confirmed that the percutaneous absorption of melatonin was effectively performed as shown in the experimental results of Table 4.
  • Examples 18 to 22 can be seen to increase the amount of transdermal absorption using a transdermal absorption enhancer. In addition, it can be seen that Examples 18 to 22 also change the transdermal absorption according to the type and amount of the additive such as transdermal absorption enhancer.
  • the crystallization inhibitor was added to the 70mL vial to dissolve, and then dissolved in a dissolution aid, antioxidant, transdermal absorption enhancer, and melatonin, and then mixed in a roll mixer for 2 hours. After leaving for 30 minutes to remove the air bubbles, the polyethylene terephthalate release film treated with silicon on the coating machine and the blended pressure-sensitive adhesive was coated to 70 ⁇ m after drying. Thereafter, after drying for 3 minutes in an oven at 80 ° C., the support layer film was laminated and pressed using a compression roller, and then a patch having an area of 10 cm 2 was produced using a patch cutter.
  • Table 5 The compounding amount according to each example is shown in Table 5 below, and then the physical properties and crystal formation of the patch were observed and transdermal absorption experiment was performed. Observation and experimental results are also shown in Table 5 below.
  • the prepared patch was confirmed that the percutaneous absorption was well performed when using the C 8-18 aliphatic derivative of the percutaneous absorption enhancer as in Examples 23 to 28 of Table 5.
  • Melatonin transdermal absorption preparation according to the present invention is capable of controlling drug release, high stability, easy storage and use, and is easy to manufacture.
  • the transdermal absorption preparation according to the present invention can significantly improve the compliance of the patient to the oral medication, and can deliver an effective amount of the drug required by the patient can be useful in the treatment of insomnia and sleep disorders.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une formulation pour absorption percutanée contenant de la mélatonine qui est un matériau pharmacologiquement actif utile pour traiter des patients atteints d'insomnie et de troubles du sommeil.
PCT/KR2017/011961 2016-10-31 2017-10-27 Formulation pour absorption percutanée pour le traitement de troubles du sommeil WO2018080214A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP17864720.2A EP3533443B1 (fr) 2016-10-31 2017-10-27 Formulation pour absorption percutanée pour le traitement de troubles du sommeil
CN201780067578.0A CN110022864B (zh) 2016-10-31 2017-10-27 用于治疗睡眠障碍的经皮吸收制剂
US16/345,948 US20210154153A1 (en) 2016-10-31 2017-10-27 Percutaneous absorption formulation for treating sleep disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2016-0143368 2016-10-31
KR20160143368 2016-10-31
KR10-2017-0138990 2017-10-25
KR1020170138990A KR102499141B1 (ko) 2016-10-31 2017-10-25 수면장애 치료용 경피흡수제제

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WO2018080214A1 true WO2018080214A1 (fr) 2018-05-03

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PCT/KR2017/011961 WO2018080214A1 (fr) 2016-10-31 2017-10-27 Formulation pour absorption percutanée pour le traitement de troubles du sommeil

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019226150A1 (fr) * 2018-05-21 2019-11-28 Wellesley Pharmaceuticals Inc. Composition et méthodes pour traiter des troubles du sommeil
JP2022532635A (ja) * 2019-05-15 2022-07-15 デーウン ファーマシューティカル カンパニー リミテッド 高含量のドネペジル又はその塩を含む経皮吸収製剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5385736A (en) * 1993-07-12 1995-01-31 Minnesota Mining And Manufacturing Company Transdermal melatonin delivery system
DE19713141A1 (de) * 1996-03-29 1997-10-30 Labtec Gmbh Transdermales System mit Melatonin
KR20110118525A (ko) * 2010-04-23 2011-10-31 아이큐어 주식회사 경피 흡수 제제
CN104940172A (zh) * 2015-06-16 2015-09-30 马建国 一种含褪黑素的透皮贴片及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5385736A (en) * 1993-07-12 1995-01-31 Minnesota Mining And Manufacturing Company Transdermal melatonin delivery system
DE19713141A1 (de) * 1996-03-29 1997-10-30 Labtec Gmbh Transdermales System mit Melatonin
KR20110118525A (ko) * 2010-04-23 2011-10-31 아이큐어 주식회사 경피 흡수 제제
CN104940172A (zh) * 2015-06-16 2015-09-30 马建国 一种含褪黑素的透皮贴片及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3533443A4 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019226150A1 (fr) * 2018-05-21 2019-11-28 Wellesley Pharmaceuticals Inc. Composition et méthodes pour traiter des troubles du sommeil
JP2022532635A (ja) * 2019-05-15 2022-07-15 デーウン ファーマシューティカル カンパニー リミテッド 高含量のドネペジル又はその塩を含む経皮吸収製剤
JP7262618B2 (ja) 2019-05-15 2023-04-21 デーウン ファーマシューティカル カンパニー リミテッド 高含量のドネペジル又はその塩を含む経皮吸収製剤

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